Background on Solubility

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Bonnie Hudson
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1 CHEM Open Notebook Science Solubility Challenge 1 For the first laboratory exercise of this semester we are going to participate in the Open Notebook Science (ONS) solubility challenge The first round of this challenge calls upon people with access to materials and equipment to measure the solubility of compounds (aldehydes, amines and carboxylic acids are a priority) in organic solvents and report their findings using Open Notebook Science. This project has been written up in Nature Proceedings: Background on Solubility Solubility is a crucial physiochemical property of organic compounds that impacts almost every laboratory procedure in organic chemistry. In addition, solubility plays a key role in pharmacokinetics and therefore, in drug development. Most organic reactions are done in solution. The solubility of reactants as well as products plays an important role in determining the reaction yield. The workup of reaction mixtures often involves liquid-liquid extraction techniques that rely on the variable solubilities of the components to isolate target compounds. As we have seen last semester, solubility is part of recrystallization as an isolation and purification technique. The most common way of purify compounds is by column chromatography methods (CC, HPLC, and GC) that use various solvents to carry compounds through a column. The identification of organic compounds by UV-vis and NMR require that a compound be dissolved in a suitable solvent prior to analysis. Solubility and Non-Covalent Interactions: Solubility is governed by non-covalent interacts between the solvent and solute. Generally, if the solvent molecules are attracted to the solute molecules by non-covalent forces they will solvate (dissolve) the solute molecules. The greater force and greater number of attractive interactions, the more soluble a solute will be. Non-covalent interactions are categorized as: 1) hydrogen bonding, 2) ionic interactions, 3) hydrophobic interactions 4) Van der Waals interactions that include dipole-dipole, and dipole-ion interactions. Non-covalent interactions are weak interactions that are temporary (reversible), selective, and sensitive to environmental conditions such as temperature and solute concentration. Because non-covalent interactions are rather complex, it is difficult to predict compound solubilities with any accuracy. In some cases where a large number of measurements with a many compounds have been made in single solvent, algorithms can be created that predict solubility based on molecular mass, molecular formula, and the functional groups present on the molecule. These types of predictive algorithms have been created for water solubility which plays a key role in pharmacology ( for example).

2 CHEM Open Notebook Science Solubility Challenge 2 Steps in determination of solubility: All sentences (directives or questions) written in bold font must be addressed in your prelab. 1) Choosing a solute. (1 point) We are going to work with organic compounds that are already in our stockroom, giving priority to aldehydes, amines and carboxylic acids. A list of stockroom chemicals (in random order) will be available on the course webpage. It is always a good idea to choose a plan B compound too. Compound name, classification (aldehyde, for example), molecular formula, SMILES representation, InChI representation, molecular mass, melting point, and safety information. Plan B compound name, classification (aldehyde, for example), molecular formula, SMILES representation, InChI representation, molecular mass, melting point, and safety information. SMILES and InChI codes can be found by searching your compound(s) in Wikipedia or 2) Choosing a suitable solvent. (1 point) Since the solvent is going to be removed from the mixture during the laboratory period, it is a good idea to choose a solvent that can be easily evaporated at temperatures below 100 C. Solvents we have on hand are: acetone, acetonitrile, 1-butanol, dimethylsulfoxide (DMSO), ethyl acetate, isopropyl alcohol (2-propanol), 1-propanol, ethanol, methanol, methyl tert-butyl ether, and water. Solvent name, classification (hydrocarbon, for example), molecular formula, SMILES, InChI, molecular mass, boiling point, density, and safety information. 3) Choosing an appropriate mixing vessel. We are going to use centrifugation to clarify precipitate as is suggested by the ONS example protocol. Therefore, at some point we are going to be transferring the mixture into a tube that fits into the centrifuge. The centrifuges we have accommodate a centrifuge tube with a capacity of 4-6 ml. Possible mixing vessels include 20 ml scintillation vial, test tube, centrifuge tube, erlenmeyers, etc Keep in mind that you will be doing four parallel measurements of solubility. Write your choice of mixing vessel and approximate volume. 4) Solvent and solute mixing. The solvent and solute will be combined together in the mixing vessel until the solution is saturated. For mixing we have a choice of manual shaking, vortexing, and or sonicating. Write a procedure for solvent + solute mixing.

3 CHEM Open Notebook Science Solubility Challenge 3 5) Clarifying the saturated solution. Excess (non-dissolved) solute must be carefully removed from the saturated solution. The model protocol suggests centrifugation is a good way to do this. Write a procedure for centrifugation of your saturated solution(s). 6) Volume of saturated solution. The volume of the saturated solution before evaporation must be recorded. Options for volume measurements of 1 ml or greater are: graduated cylinder (smallest volume is 10 ml), pipettes (1, 5, and 10 ml), or syringe (1, 5, or 10 ml capacity). Write a procedure for measuring volume of saturated solution into the evaporation vessels. 7) Obtaining the mass of the evaporation vessel. Obtaining an accurate mass of the solute after evaporation is very important. In fact, we are going to calibrate our balances for this experiment. Choose an evaporation vessel. 8) Obtaining the mass of solution before evaporation Obtaining an accurate mass of the solution before evaporation is necessary to report the solubility in terms of g/100g solvent. 9) Initial evaporation of solvent. We are going to evaporate the solvent in a hot water bath to obtain an initial mass of solute during the laboratory period. Write a procedure for evaporation of saturated solution. 10) Obtaining the mass of the evaporation vessel and solute. This is where you find out just exactly how much of your solute was dissolved. 11) Prolonged evaporation of solvent. We cannot assume that the sample is completely dry after an initial solvent evaporation in a hot water bath. Prolonged drying can be performed by simply leaving the vessel containing the residue in the open. More efficient ways of drying involve placing the evaporation vessel in a drying oven and/or in a container with a desiccant. 12) Obtaining the mass of the evaporation vessel and solute after prolonged evaporation. You should compare this value to step 10 and make any necessary adjustments. You may need to do additional measurements to assure that the mass has stabilized.

4 CHEM Open Notebook Science Solubility Challenge 4 13) Duplicate experiments. A final consideration is duplication of results. In an analytical procedure, the more parallel measurements that are done the better quality is the data received. As you are well aware, it is very difficult to have confidence in the accuracy a single measurement done on a single experimental procedure. The centrifuges need to be balanced so it is practical to do an even number of parallel experiments for this lab exercise. We will do four parallel experiments. 14) Procedure entry: According to the ONS challenge rules, the procedure used to determine solubility must be entered into the ONS challenge Wiki. A typed procedure must be ed to <jbfriesen@dom.edu> as part of the Lab Report. An ONS solubility challenge link may be found at 15) Calculations: The raw results should include: Mass of the empty evaporation vessel. Volume of the saturated solution before evaporation. Mass of the saturated solution before evaporation. Mass of the solute. Sample Calculation (2 points) Given the following data: Mass of the empty evaporation vessel = Volume of the saturated solution before evaporation = 5.00 ml Mass of the saturated solution + vessel before evaporation = Mass of the solute + vessel = Molecular mass of solute: grams/mole Solvent Density: g/ml Calculate solubility in g (solute)/ml (solution) using the volume of the saturated solution before evaporation? Convert g/ml into molarity = moles/liter? Calculate the solubility in g(solute)/100g(solution) using the mass of the saturated solution before evaporation? Calculate the absolute uncertainty for your measurement of g/100g given a balance precision of +/- 1 mg? Calculate the relative uncertainty for your measurement of g/100g given a balance precision of +/- 1 mg? (Help for calculating uncertainties is posted on course webpage) 16) Data entry: According to the ONS challenge rules, the solubility data must be entered into the ONS challenge spreadsheet. The appropriate solubility data must be included in the lab report. Links to the cumulative list of results is on the ONS solubility challenge homepage

5 CHEM Open Notebook Science Solubility Challenge 5 Prelab Questions: (The question number refers to the procedure step.) Intro - (1 point) What is Open Notebook Science? How does it differ from Closed Notebook Science? Q1 - (1 point) What are SMILES and InChI? How are they useful? Q2 - (1 point) What else besides boiling point is a useful criteria for choosing an appropriate solvent? Q3 - (1 point) a) How will we determine if the solution is saturated? b) Why might solutes with melting points between 25 and 100 C present a challenge? Observations: (4 points) You will hand in a copy of your observations at the end of the lab period like last semester. Unlike last semester you will not be given a specific set of questions to respond to. A general guide to recording observations is found in the laboratory syllabus. Report: A typed procedure must be ed to <jbfriesen@dom.edu> as part of the Lab Report. (3 points) Include a table of: -solute -solute SMILES -solute type (aldehyde, carboxylic acid, amine, etc ) -solvent -solvent SMILES -solvent density -mass of empty evaporation vessel (each experiment): -volume of solution (each experiment): -mass of evaporation vessel + solution (each experiment): -mass of evaporation vessel + solute (each experiment): -solubility g/ml using volume of solution - average concentration in M (moles/liter) -average solubility g/100g solvent using mass of solution.

6 CHEM Open Notebook Science Solubility Challenge 6 The following questions will be answered as part of the lab report (5 points). The question number refers to the procedural step. Intro) Why does water solubility matter so much in pharmacology (hint: ADME)? Intro) Describe the non-covalent forces that determined the solubility (or insolubility) of your solute in your chosen solvent. Q1) Why may liquid (liquid at room temperature) solutes be more difficult to work with than solid solutes? Q4) Does order of addition matter (solvent to solute or solute to solvent)? Q5) Why centrifugation and not filtration? Q10) Why can t we assume that the sample is completely dry after the initial solvent evaporation in a hot water bath? Q11) Your samples may weigh more after prolonged drying than they did after the hot water bath. What is the explanation for this? Q12) Accurate is a term that is often misused. Define, compare and contrast accuracy and precision in the context of this experiment. Q15a) What is the absolute uncertainty for your measurement of g/100g given a balance precision of +/- 1 mg? Q15b) What is the relative uncertainty for your measurement of g/100g given a balance precision of +/- 1 mg?

12A Lab Activity Notes

12A Lab Activity Notes Lab Activity 12 In this experiment, RX reacts with a base. The methoxide ion (CH 3 O - ) is a small, strong base. The tert-butoxide ion ((CH 3 ) 3 CO - ) is a large, strong base.