A Review of Some of the Solubilities of Organic Compounds in Non-Aqeuous Solvents.

by

Tim Bohinski




Abstract

Since working in the Bradley research group at Drexel University much emphasis has been put on solubility determination of Ugi reagents and Ugi products in non aqeuous solvents. This experimental information will contribute to a solubility model specific for the Ugi reactions. By doing this type of research I have chosen to look into the amount of solubility data that already exists in non-aqeuous solvents. The information was very scarce and many types of research methods were used; some better then others. This paper provides detail into the solubility determinastion methods, the types of solvents used, the compounds that have been used, the way the data is reported, and what type of information any of the data may tell us.

Introduction

The CRC Handbook of Chemistry and Physics states solubility as; "Solubility is a quantity expressing the maximum concentration of some material that can exist in another liquid or solid material at the thermodynamic equilibrium at specified temperature and pressure."(Lide 2008)Private access Solubility data is always wanted in numerous types of experiments and procedures."Since a wide variety of experimental procedures, such as surface studies, extraction, and fractional crystalllization, require accurate solubility data, determination of the solubilites of the higher acids in common solvents is of appreciable value."(Ralston 1942) Private access Solubility data can even be applied to biological applications. For example, if there is a chemical spill in the environment it can be very useful to understand how the contaminant may interact with its surroundings. The solubility information for the known contaminant can lead to a successful type of treatment. "The solubilities of domoic acid in different media are important parameters for the understanding of the biological
action and environmental behavior of this newly discovered and seasonally dangerous marine toxin." (Falk 1991) Below is a picture of domoic acid taken from Chemspider.

domoic_acid.gif

"The solubility of solid compounds in solvents and solvent mixtures plays a key role in all crystallization processes." Crystallization plays an important role in various sectors of industry including catalysts, proteins, agrochemicals, and especially pharmceuticals. The yield of any process within these industries is ultimately controlled by the solubility. (Gracin2007). Many different areas of chemistry and industry rely on solubility data and therefore it is worth researching into. However most of the research that is done was usually done in aqeuous solvents, and not pure non-aqeuous solvents. Also there is a large number of papers that predict solubilities using mathematical and computer generated models. This paper does not take interest into the prediction of solubility. This paper purely is based upon experimental results from around the world. Since this is the case it is worthwhile to note some of the research that has been obtained in non-aqeous solvents.
In the Bradley lab emphasis has been put on the solubilities of organic compounds in varying solvents. All of the data acheived in the Bradley lab has been experimentally determined rather then predicted, and it also has been compared with other solubility data that may already been found in other research. This data will help build a model that can successfully predict a Ugi reaction, and since there are many combinations of Ugi reactions this data can be very helpful and save much time. The Ugi reaction is as follows, where a aldehyde/ketone, isonitrile, amine, and carboxylic acid are brought into solution to try and create a Ugi product.
550px-Ugi_Reaction_Scheme.png
(CombiUgi)
Searching for solubility data of organic compounds in non-aqeuous solvents proved to be quite the task. Many of the searches yielded few or no results.Much of the data dealt with organic compounds in aqeous systems. However enough information was still found to gain an understanding of solubility, and the methods from which the results arise. The variety of methods have also proven insight into trying to determine solubilities of compounds in the Bradley Lab.

Solubility Determination Methods

When determining solubilities it is very helpful to know what type of method to apply to varying systems. Each method is used in different situations depending on the solute and the solvent.The most common methods for solubility determination are discussed below. They range from a very simple evaporation technique, to more analytical techniques like UV/VIS, and gas-liquid chromatography, and even to a laser monitoring observation technique.
The simplest method and most widely used method based on this research is the evaporation technique. Briefly, saturated solutions are created and left to evaporate in a speedvac for a certain amount of time. Exp207. The speedvac is a apparatus that spins at high velocities and its chamber can be pressurized. This is the main technique used for most of the solid compounds in the Bradley lab. However some problems can occur as seen in Exp209. The pressure not only affects the evaporation rate but also the boiling point of most of the solutes. Some solutes can be very volatile under low pressures within a vacuum. " The boiling point of a liquid varies according to the applied pressure."(Brittanica 2008) Knowing the time it takes to evaporate the solvent from the solution can greatly reduce the amount of error in the solubility data of the compounds. The aim of this experiment was to reduce the amount of time that solutions would be kept in the speedvac since the solutes' boiling points can significantly drop under pressure. This would give a false solubility measure. Since taking this variable into consideration a reduced press. b.p calculator has been used for organic compounds to see if under the conditions of the speedvac if the volatility of the solutions must be worried about.
Another problem is seen in Experiment001 performed by Jenny Hale. "This method worked well for the barely soluble solutes, but did not work for the very soluble compounds as the volume of the solvent increased substantially as more solute was dissolved. This was particularly noticeable for the vanillin as my gloves became wet from lost solvent as the tube became full." Jenny. From my own experience with solubility determination, Jenny Hale makes a noticeable observation. The very soluble compounds would increase the volume of the system and eventually there wouldn't be much more room to add additional solute. A solution could be to increase tube size or decrease volume, but just because the evaporation method is a simple one doesn't necessarily mean problems won't occur. In a research paper from 1966, solutions are prepared by adding excess solute to a solvent. Aliqouts are taken of the solution and left to equilibriate for several days with periodic agitation. A sample of the saturated solutions were then evaporated using dry air. (Hancock, 1966) The method was able to determine many different meta- and para- substituted benzoic acids. Since this method is inexpensive, requires little analysis,and little labor, a scientist can see why it is a practical method to apply to a large number of solutes.

Gas-Liquid Chromatography also know as GLC or GC, can also be used to identify solubilites of organic compounds. "Liquid samples are vaporized before injection into the carrier stream. The gas stream is passed through the packed column, through which the components of the sample move at velocities that are influenced by the degree of interaction of each constituent with the stationary nonvolatile phase." (Britannica) .Since the retention times of the solute and solvent will be different a concentration of solute can be calculated. One compound that I have experimented in the Bradley lab with was p-nitrobenzaldehyde (PNBA). The solubility data for PNBA in many different non-aqeuous solvents has also been researched into. The research focused on the kinetics of the Wittig reaction. The effects of the solvents play a determining role in the Wittig reaction."In investigating reactions involving carbanions, negatively charged organic species, Wittig discovered a class of organic phosphorus compounds called ylides that mediate a particular type of reaction that became known as the Wittig Reaction."(Brittanica) Solubility data plays a practical role in research and not just as a data figure in any old chart. In this case excess PNBA was added to 5ml of the solvents. The solution was agitated for one day, and the solubilites were then determined by using GLC. (Maccorone 1982) Exp212 showed experimentally by the evaporation method that the solubility of PNBA was 1.08M. The Wittig Reaction paper does not have value at this data point but when it is extrapolated the value is 1.081M. This confirms that both methods are very precise amongst each other. No data in a handbook exists for this measurement but two seperate experiments agree on the solubility of PNBA in chloroform.
A final technique widely used is UV/VIS spectroscopy. The relationship between the absorbance and molar absorbtivity can help us calculate the concentration of saturated solution and thus tell us information about the solubility. Since at a specific wavelength the absorbance will be maximum, we can determine from this information the molar absorbtivity, and then finally the concentration of our saturated solution. The above paper also used UV/VIS to determine solubility. UV/VIS can also determine solubilities of different solutions as well, including the solubilities of Lutein and carotenoids. Saturated solutions were made and a calibration curve was generated as well. By making a creating a calibration curve, and utilizing Beer's Law, solubilities were given by the equation: Absorbance*dilution factor/ molar absorbtivity. Craft 1992The paper by Craft is an example of how physical data information can be scarce for compounds in non-aqeuous solvents. The research that has been compiled within this paper shows like Craft, that the data available for organic compounds in non-aqeuos solvents is also small. He notes that the lack of this information makes it more difficult to create analytical methods for carentoid research.
Another interesting and useful way to use UV/VIS is applying it to the stability of compounds. "Stability was monitored for 10 days at room temperature by measuring absorbance changes at the wavelength maximum."Craft 1992 Carotenoid degradation was accompanied by decreases in absorbances"Craft 1992 Since it is possible that degraded compounds gave decrease absorbances this also means that the concentration of the solution would also change. This fact can play a role when determining the solubility of a compound that needs to be kept under certain conditions. For example if the chemical we are investigating is known to exhibit photdecomposition, and we dont acheive desirable results, we can ask ourselves the question if the chemical was stored in the light for an extended period of time. Degradation or possible sources of a chemical decomposing should be closely noted before trying to determin solubility for it, since this can lead to a waste of time.
A very interesting paper discussed the solubility of domoic acid in water and varying solvents, for its biological application. Its solubility was analyzed by UV/VIS spectroscopy. "The solubilities of domoic acid in different media are important parameters for the understanfding of the biological actiona and environmental behaviour of this newly discovered and seasonally dangerous marine toxin." (Falk 1991). By determining solubility of compounds like domoic acid, methods to isolate and purify samples can be devised. A very real world problem can be solved by understanding the solubility of some compounds.
A final technique that I came across is based on a laser monitoring obeservation technique. The research conducted used the chemical 2-(4-Ethylbenzoyl)benzoic acid (EBA), where the solubility was measured with the last crystal disappearance method.In the experiments.
The basis of the laser method adds pre-weighed masses of a solid, to an agitated solution at a specific temperature. All masses are exactly known. After the solute went into solution more compound was added. If the solution was clear after the addition of all the solute, the laser intensity through the solution would be at a maximum. If the solution wasn't clear, the laser would be below its maximum. Thus the laser detection would give information pertaining to the dissolution of the solute.(Su 2008).There are many different approaches to obtain solubility data for a given compound. Depending on the compound, different approaches can be used, as well as how accurate you want your information to be, can influence your methodology.

Solvents

The focus of much organic compound solubility data was in aqeuous systems. However many non-aqeuous solvents have been used including methanol, ethanol, chloroform, benzene, toluene, THF, dichlorbenzene. A basic rule in organic chemistry is that “like dissolves like.”Britannica For example polar solvents usually dissolve other polar compounds easily, whereas non-polar solvents can have a harder time to dissolve polar compounds. The role of the solvent plays an important role when determining what type of environment is the best suitable for the Ugi Reaction.. "Once we have Ugi products in hand in pure form from a reaction in methanol we will simply measure their solubility in other solvents, starting with ethanol, acetonitrile, THF and toluene. Low solubility will not guarantee that the Ugi reaction will proceed smoothly to produce a precipitate when carried out in a given solvent but it will certainly be a great starting point." Bradley 2008 " Rajarshi made the point that models predicting solubility in non-aqueous systems are needed and could be quite helpful to the chemistry community." Bradley 2008 Not only will the Ugi Products be tested for their solubility but it is very useful information that ugi reagents will be measured as well for their solubility. By creating this solubility database the model that Rajarshi will create will be based on the in-lab results. By determining what solvent is best for the combination of reagents, a possibility for more successful Ugi Products can be made.

THF is chosen to dissolve substituted benzoic acids because it allows for the formation of hydrogen bonds by dissociating the acid into individual molecules, also becuase it reduces solute-solute interactions. Hancock 1967 "Coassociation of solute with solvent occurs when intermolcular bonds can be formed and association of the solute is thereby reduced" Hnacock 1967 By reducing the possible solute-solute reactions, the solvent is allowed to react with the solute, and therefore achieve solubility of the solute. In a similar study benzene and cyclohexane were also used as solvents due to there similarities in structure and dipole moments. There resutls showed that for each of the subsitituted acids the solubility was greater in benzene then in cyclohexane. Also the meta- positions were more soluble then there para- counterparts, in benzene. The solubilites of the m- and p-aminobenzoic acids were also studied and it showed cyclohexane to be a better solvent for the meta- positions and benzene to be a better solvent when the group was in the para position. Hancock 1966 The slight differenent in structure between para and meta substituted rings can give the compound slightly different polarties, thus enabling one solvent to be better then the other.

Solutes

"The Ugi reaction has proved to be a convenient way to quickly create diverse libraries of compounds. It involves the reaction of an amine, an aldehyde, a carboxylic acid and an isonitrile typically in methanol at room temperature" Bradley 2008. Since large libraries of compounds are formed from Ugi reagents, it is necessary to find pre-existing solubility data for the reagents to help build the model from which Ugi products can be formed with the greatest success.
Since it would take a very long and immense search to look for the enitre data for all ugi reagents in non-aqeuous solvents, I have chosen to focus on the aromatic aldehydes and carboxylic acids. I found the Belistein databse to be the most useful when searching for this data. Throughout the research I have found many different substituted benzoic acids but barely any aromatic aldehydes. As I have said prior in this paper the solubility information is very scarce, however aqeuous solubility data is almost always reported. Despite what it seemed like unnattainable data, I was able to find some data for this review. The following data table is a compilation of the solubility data found in other research papers for the organic compounds in many different non-aqeuous solvents. The data table gives the name of the solute followed by the solvent it is dissolved in. The solubility is then reported. In the next row the way the data was reported was given along with the temperature the data was found at. The data is reported in many ways, from Molarity to g/kg of solvent. The most common way to report solubility in this report is molar fraction. Despite that there are more measurements at g/kg, molar fraction was found in a wider range of papers. Here is a spreadsheet that contains all of the results I have found during this research. Beilstein was used to sift through aromatic aldehydes and aromatic carboxylic acids are being searched for now. Other data for other organic compounds was also found and put into this spreadsheet. Not all of the organic compounds used in the Ugi reaction has been looked over. This paper only sheds light on some of the solubility findings of certain organic compounds.
A great example of comparing results found within the Bradley lab those found in published research is the solubility of para-nitrobenzaldehyde in chloroform. The solubility of PNBA was measured at different temperatures amongst various solvents including solvents that we have used in Exp208. The following solvents were used in both experiments; toluene, chloroform, ethanol, and acetonitrile. Exp208 was performed by making saturated solutions and using the evaporation method to determine the solubility.

external image ImagesHandler.ashx?id=526
Maccarone and Perrini also made saturated solutions but used GLC to analyze the solubility. Like stated previously the results of the solubility in chloroform were almost dead on. Both research papers can therefore help support each other.

References

1) "Definitions of Scientific Terms", in CRC Handbook of Chemistry and Physics, 88th Edition (Internet Version 2008), David R. Lide, ed., CRC Press/Taylor and Francis, Boca Raton, FL.
2) Ralston, A.W.; Hoerr, C.W. J. Org. Chem.; 1942; 7(6); 546-555
3)Bradley, J.-C., UsefulChem EXP207 http://usefulchem.wikispaces.com/EXP207
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5)Reduced Pressure Boiling Point Calculator information found at http://www.pirika.com/chem/TCPEE/BP/RPBP.htm. Nov. 2008.
6) Bradley, J.-C., Hale, Jenny. ONS Challenge JennyHale-1. http://onschallenge.wikispaces.com/JennyHale-1
7) Hancock C.K., Pawloski J.N., Idoux J.P. "Quantitative Solubility-Structure Relationships for Some meta- and para- Substituted Benzoic Acids in Benzene and in Cyclohexane" The Journal of Organic Chemistry. 31 (11).3801 (1966)
8) Hancock C.K, Idoux J.P. "Quantitative Solubility-Structure Relationships for Some meta- and para- Substituted Benzoic Acids in p-Dioxane and in Tetrahydrofuran" The Journal of Organic Chemistry.32 (6). 1961 (1967)
9) "Wittig, Georg." Encyclopædia Britannica. 2008. Encyclopædia Britannica Online. 20 Nov. 2008 <http://www.search.eb.com/eb/article-9077299>.
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Canadian Journal of Chemistry. 1991, 69, 1740-1744
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Journal of Agricultural and Food Chemistry.1992,40, 431-434.
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19)Domoic Acid picture; http://www.chemspider.com/Chemical-Structure.4445428.html Nov. 2008
20) PNBA picture; http://www.chemspider.com/Chemical-Structure.526.html Nov. 2008