recrystallization

=Recrystallization Project=

Participants
Jean-Claude Bradley, Andrew Lang, Matthew McBride, Rida Atif

Objective
The purpose of this project is to provide concrete examples of how Open solubility and melting point datasets and models can be used to recommend solvents for the recrystallization of small neutral organic compounds. Priority will be given to compounds that are commonly recrystallized in organic chemistry teaching labs (i.e. benzoic acid, cinnamic acid, dibenzalacetone).

Concepts
solubility, melting point, recrystallization, modeling, benzoic acid, cinnamic acid, dibenzalacetone, teaching labs, salicylic acid, acetylsalicylic acid

Databases

 * 1) [|Manually Validated Recrystallization Sheet for bin sums 10]
 * 2) [|Recrystallization Sheet for bin sums 9-10 for the compounds with recrystallizations found in literature]
 * 3) [|Recrystallization Sheet for 50 Entries with sol at bp represented by g/mL]
 * 4) [|Recrystallization Sheet for 50 Entries with Bin Sums and Sorting] [[file:Recrystallization Sheet 50 Entries .xlsx|Excel Sheet]] [| Google Doc with no bin sums]
 * 5) [|Master Recrystallization Sheet with bins] [[file:onschallenge/RecrystallizationMatrix results.xlsx|Excel Sheet]]
 * 6) [|Master Recrystallization Sheet]
 * 7) [|Solubility at boiling] (calculates the theoretical recrystallization yield from the measured solubility at boiling)
 * 8) [|Recrystallization examples] (specific examples of recrystallization in the literature for compounds of interest - if available the yield is recorded)
 * 9) [|RSC Recrystallization Project (SUNY Potsdam)]
 * 10) [|OCPM database] (various properties and descriptors related by published formulas)
 * 11) [|Ethanol/Water solubilities at Room Temperature]
 * 12) [|Dibenzalacetone]
 * 13) [|Cinnamic Acid]
 * 14) [|Benzoic Acid]
 * 15) [|Salicylic Acid]
 * 16) [|Acetylsalicylic Acid]
 * 17) [|Library of Dibenzalacetone derivatives]
 * 18) [|Literature information on Dibenzalacetone derivatives]
 * 19) [|Dibenzalacetone derivatives UV data]
 * 20) [|Dibenzalacetone derivatives bioactivity]

Abstract
The construction and deployment of a system to recommend solvents for the recrystallization of neutral organic compounds is described. Key components include collections of open experimental solubility and melting point measurements. In the absence of experimental data both the room temperature solubility and melting point can be predicted from models described herein. The melting point is required to estimate the solublity at the boiling point of the solvent. The solubility model is based on the calculation from experimental measurements or estimation of Abraham descriptors from CDK descriptors using a Random Forest optimization. A similar approach is used for melting point estimation. The final ranking of solvents for a particular solute is based on binning of the estimated recovery yield, the boiling point of the solvent and the solubility at boiling. All of the input data, descriptors, algorithms and output data are open for reproducibility and encouraging re-use. For convenience data can be dowloaded in raw form or queried through various interfaces, including a smartphone app.

Introduction
Recrystallization is often a preferred means of purifying solid chemicals because of its simplicity and scalability.[1] However, for new compounds or compounds where it is difficult to find a prior report of recrystallization conditions, solvent selection is largely trial and error with no guarantee of a quick resolution.[2] Although much more cumbersome and more difficult to scale, chromatography is generally the chemist's first choice since the desired compound can usually be separated from impurities in a predicted time frame. If there was a convenient way to recommend recrystallization solvents for a wide variety of compounds, it could be a practical way of saving time by avoiding more costly and less scalable purification methods.

In principle, the recovery yield for a typical recrystallization can be calculated by subtracting the solubility at the end temperature (generally 25C) from the solubility at boiling. Even for common solutes solubility measurements in a wide range of recrystallization solvent candidates are generally incomplete at room temperature and much more difficult at the boiling point of the solvent. Consequently, a model for predicting solubility of neutral organic compounds at room temperature is reported here. The prediction of solubility at boiling is made by assuming that the molten solute is miscible in the solvent and that the log of the solubility varies with the inverse temperature in Kelvin.[3] Because of its necessity for the calculation, a melting point model is also reported here.

A primary aim of this project is to ensure that the input and output data as well as the models themselves and their associated molecular descriptors are provided as Open Data.[4] Collections of experimental solubility and melting point measurements are provided here as Open Data (CC0 license).[5,6] When available, these data points are used in calculations. Otherwise predictions from the models described here are used to recommend solvents for the recrystallization of a particular solute.

Test Cases
1. Benzoic acid 2. Cinnamic acid 3. Dibenzalacetone

Working Notes
Benzoic acid is recrystallized from water. [|Horowitz03] [|Weichman74] [|Amsterdamsky98] [MJM] Biphenyl and Naphthalene are recrystallized from hexane and then methanol. [|Sadek11] [MJM] Cinnamic acid is recrystallized from water. [|Buckles50] [MJM] Dibenzalacetone is recrystallized from ethanol. [|Hawbecker78] [MJM] Chalcones (prepared from acetophenone and benzaldehyde derivatives) [JCB] Salicylic acid and Acetylsalicylic acid [JCB]
 * What are some common compounds purified by recrystallization in teaching labs?**
 * What commercial or __#|Open Source software__ tools are available to select solvents for recrystallization?**
 * What commercial or Open Source software tools are available to predict solubility in organic solvents at room temperature?**
 * What commercial or Open Source software tools are available to predict solubility in organic solvents at the boiling point?**

Using only a melting point (no experimentally determined solubility) Model003 identified the following as good candidates for recrystallizing dibenzalacetone (>80% predicted recovery and a convenient boiling point of 60-80C): hexane, cyclohexane, 2-propanol, trifluoroethanol, methanol, ethanol and the ethanol/water mixtures. Of these ethanol would be most preferred since it is miscible with water (a contaminant from the synthesis) and has a higher predicted recovery yield than methanol. [[|dibenzalacetone sheet] ][JCB] According to Model003 solely, the following solvents were identified as good candidates for recrystallizing benzoic acid (given a predicted recrystallization yield of at least 80% and a boiling point between 60-100C for convenience): water, heptane, cyclohexane, hexane, carbon tetrachloride, benzene, and various ratios of ethanol/water mixtures. Of these solvents, all but heptane and water would be preferred because they have a convenient boiling point of up to 80C. Although water and the ethanol/water mixtures are predicted to yield high amounts of benzoic acid back, they are rather inconvenient to use because they are difficult to completely dry from the crystals. The most optimal candidate for recrystallizing according to the model is 2,2,4-trimethylpentane, however that is not a very common solvent. [[|Benzoic Acid Sheet]] [RA] According to Model003 only, the following solvents were identified as good candidates for recrystallizing cinnamic acid (given a predicted recrystallization yield of at least 80% and a boiling point between 60-100C for convenience): water, heptane, cyclohexane, hexane, carbon tetrachloride, benzene, 2-butanol, 1-propanol, and various mixtures of ethanol/water. Of these solvents, cyclohexane, hexane, carbon tetrachloride, benzene, and ethanol/water mixtures would be preferred because they have a convenient boiling point of up to 80C; the other solvents boil at significantly higher temperatures. Even though the ethanol/water mixtures are predicted to give high recrystallization yields, they would be inconvenient to use because they are difficult to completely dry off from the crystals. One of the most optimal solvents to recrystallize cinnamic acid according to the model is 2,2,4-trimethylpentane, however it is not a common solvent in many teaching labs. [[|Cinnamic Acid Sheet]] [RA] For the most part the experimentally determined and AD model calculated values __#|agree__ with the Model003 predictions and do not change the solvents recommended solely from Model003. Specifically the favored solvent ethanol has an 89% predicted recovery yield from Model003, 94% from the AD model and 92% from the experimental room temperature value. Ethyl acetate is predicted to have an inferior recovery yield by all three estimates (69-79%), which is of significance since it is a commonly used solvent to purify this compound.[[|dibenzalacetone sheet] ][JCB] Model003 identified, using only a melting point and no experimentally measured solubilities, the following solvents as ideal (>80% predicted recovery and a boiling point of 60-80°C) for recrystallizing salicylic acid: hexane, cyclohexane, carbon tetrachloride, 1-chlorobutane, benzene, ethanol/water(10:90)vol, ethanol/water(20:80)vol and ethanol/water(30:70)vol. The following solvents had a predicted recovery of >80% and boiling points of 80-100°C: 2,2,4-trimethylpentane, heptane, fluorobenzene and 1,2-dichloroethane. Based on this analysis, hexane, cyclohexane, carbon tetrachloride, 1-chlorobutane or benzene would be the preferred solvent for recrystallizing salicylic acid. Water is difficult to remove from product so the ethanol/water mixtures are not preferred. [|Salicylic acid sheet] [MJM] Model003 identified, using only a melting point and no experimentally measured solubilities, the following solvents as ideal (>80% predicted recovery and a boiling point of 60-80°C) for recrystallizing acetylsalicylic acid: hexane, cyclohexane, carbon tetrachloride, ethanol/water(10:90)vol, ethanol/water(20:80)vol, 1-chlorobutane, ethanol/water(30:70)vol, benzene, ethanol/water(40:60)vol, ethanol/water(50:50)vol, ethanol/water(60:40)vol, ethyl acetate, ethanol/water(70:30)vol, 2-propanol, ethanol, ethanol/water(80:20)vol, acetonitrile, butanone, ethanol/water(90:10)vol. Based on this analysis, cyclohexane, carbon tetrachloride, 1-chlorobutane, benzene, ethyl acetate, 2-propanol, ethanol, acetonitrile or butanone would be the preferred solvent for recrystallizing acetylsalicylic acid. [|Acetylsalicylic acid sheet] [MJM]
 * What solvents did Model003 suggest would be good for recrystallizing dibenzalacetone?**
 * What solvents did Model003 suggest would be good for recrystallizing benzoic acid**
 * What solvents did Model003 suggest would be good for recrystallizing cinnamic acid?**
 * How did the predicted recrystallization solvents compare with experimentally determined and AD model calculated solubilities at 25C?**
 * What solvents did Model003 suggest would be good for recrystallizing salicylic acid?**
 * What solvents did Model003 suggest would be good for recrystallizing acetylsalicylic acid?**

Discussion
Benzoic acid has been recrystallized from ethanol (94% yield), water (60% yield), 75:25 ethanol/water (95% yield), 50:50 ethanol/water (88% yield), and 25:75 ethanol/water (92% yield). [[|Hightower06]] [MJM] Benzoic acid has been recrystallized in 41% yield from ethanol/water(40:60)vol. [[|Lab02]] [RA] Benzoic acid has been recrystallized in 79% yield from water. [[|Lab02]] [RA] Cinnamic acid has been recrystallized in 71-86% yields from water. [[|SUNY11]] [RA] Dibenzalacetone and analogs have been recrystallized in 50-80% yields from ethyl acetate.[[|Tully01] ][JCB] Dibenzalacetone has been recrystallized in 95% yield from a hexane/ethyl acetate mixture. [[|Franco12]] [MJM] Dibenzalacetone has been recrystallized in 80% yield from rectified spirits. [[|Vanchinathan11]] [MJM] Dibenzalacetone has been recrystallized from ethyl acetate. [|Palaniappan12] [MJM]
 * What solvents have been used to recrystallize benzoic acid and what are the reported yields?**
 * What solvents have been used to recrystallize cinnamic acid and what are the reported yields?**
 * What solvents have been used to recrystallize dibenzalacetone and what are the reported yields?**
 * What solvents have been used to recrystallize DNP derivatives and what are the reported yields?**